Most foreign compounds which are acted on by the microsomal mixed- function oxidase system are soluble to only a limited extent in water at physiological pH. The interactions of water-insoluble substrates with these enzymes have been studied extensively in vitro, but generally only with the aid of solubilizing agents designed to bring the substrate into aqueous solution. Previous investigations associated with this project indicated that the most suitable vehicle for the introduction of highly insoluble compounds such as biphenyl and benzpyrene to microsomal mixed-function oxidases was carboxymethyl cellulose (CMC) in which the substrate was dispensed as a fine suspension. Using CMC as a carrier for biphenyl, the response of biphenyl 2- and 4- hydroxylase to animal pretreatment with 2,3,7, 8- tetrachlorodibenzo-p-dioxin was studied in hepatic and extrahepatic tissues of the rat, rabbit and guinea pig.